WO2022005169A1 - Composition injectable comprenant des dérivés de gnrh - Google Patents
Composition injectable comprenant des dérivés de gnrh Download PDFInfo
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- WO2022005169A1 WO2022005169A1 PCT/KR2021/008187 KR2021008187W WO2022005169A1 WO 2022005169 A1 WO2022005169 A1 WO 2022005169A1 KR 2021008187 W KR2021008187 W KR 2021008187W WO 2022005169 A1 WO2022005169 A1 WO 2022005169A1
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- WIPO (PCT)
- Prior art keywords
- sorbitan
- weight
- injectable composition
- group
- composition
- Prior art date
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- 239000007972 injectable composition Substances 0.000 title claims abstract description 48
- 101150108262 gnrh1 gene Proteins 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 120
- 239000003814 drug Substances 0.000 claims abstract description 59
- 239000004973 liquid crystal related substance Substances 0.000 claims abstract description 58
- -1 sorbitan unsaturated fatty acid ester Chemical class 0.000 claims abstract description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 44
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims description 44
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- HJNZCKLMRAOTMA-BRBGIFQRSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(2s)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(2-methyl-1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydr Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=C(C)NC2=CC=CC=C12 HJNZCKLMRAOTMA-BRBGIFQRSA-N 0.000 claims description 3
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Definitions
- the present invention relates to a sustained-release depot formulation containing a GnRH derivative as a pharmacologically active substance and an injectable composition comprising the same.
- a representative pharmacologically active substance suitable to be designed in the form of a sustained-release preparation includes a GnRH derivative.
- GnRH derivatives can be used for prostate cancer, breast cancer, ovarian cancer, endometriosis, fibroids of the uterus, polycystic ovaryosis, hirsutism, precocious puberty, gonadotropic pituitary adenoma, sleep apnea, irritable bowel syndrome, and premenstrual syndrome.
- sex hormone-dependent diseases such as benign prostatic hyperplasia or infertility.
- Lupron ® Depot which contains leuprolide acetate as a pharmacologically active substance.
- Lupron ® Depot is widely used as an intramuscular and subcutaneous injection using biodegradable PLGA [poly(lactic-co-glycolic acid)] microspheres as a sustained-release substrate.
- biodegradable PLGA poly(lactic-co-glycolic acid)] microspheres as a sustained-release substrate.
- PLGA microspheres stay in the body for a certain period of time and are decomposed into lactic acid and glycolic acid to continuously release the encapsulated pharmacologically active substance, thereby exhibiting a sustained-release effect (US Patent No. 5,480,656).
- the PLGA microsphere manufacturing process has disadvantages in that it is complicated and difficult, and the encapsulation efficiency of the pharmacologically active material is significantly lowered.
- PLGA fine particles are difficult to filter and melt at a temperature of 40° C. or higher, the method generally used for aseptic treatment cannot be applied, so there is a difficulty in performing the process under highly sterile conditions.
- it is necessary to additionally perform a complicated process in which two or more different types of microspheres are prepared and mixed in order to create an ideal sustained-release pattern International Patent Publication No. WO 2005/074896
- the economic cost due to the inefficient process increases. .
- acetic acid impurities and acid decomposition substances from PLGA microspheres cause inflammatory reactions and decrease in cell proliferation rate (K. Athanasiou, GG Niederauer, and CM Agrawal, Biomaterials, 17, 93 (1996)), 10 ⁇ 100 Due to the nature of the product, which requires a large amount of intramuscular and subcutaneous administration by suspending microspheres in an aqueous solution, pain or tissue damage occurs at the injection site.
- the GnRH derivative (leuprolide acetate) sustained-release injection introduced to compensate for the shortcomings of the PLGA microsphere sustained-release formulation is ELIGARD ® .
- ELIGARD is widely marketed as a subcutaneous injection using poly(DL-lactide-co-glycolide) and a GnRH derivative (leuprolide acetate) having a protected carboxyl terminal group dissolved in N-methyl-2-pyrrolidone (NMP).
- NMP N-methyl-2-pyrrolidone
- Eli guard main ® is administered by subcutaneous after dissolving the biodegradable polymer a polar aprotic solution to prepare a liquid composition, and some improvement in the disadvantages of solid dosage forms having PLGA microspheres (U.S. Patent No. 6773714 No.).
- the product does not provide a complete pre-filled injection device, so it is very convenient to use and has disadvantages in that drug stability in a mixed solution is low.
- the kit provided by this product consists of two connectable syringes and devices for mixing, preparation and injection.
- a complicated process of about 10 steps or more is required to prepare the final mixed solution, and there is a difficulty in completing the preparation and administration within 30 minutes.
- the product requires a separate refrigeration storage device due to storage conditions, and if the final mixed solution cannot be refrigerated, it cannot be used for more than 5 days.
- the formulation did not improve the high initial drug release phenomenon, which is a general disadvantage of PLGA formulations, but rather showed a higher initial drug concentration than Lupron ® Depot, a PLGA particulate formulation (US Patent No. 6,773,714).
- Initial drug concentrations significantly above the drug functional range are not functionally or toxicologically desirable.
- GnRH derivatives are a mechanism in which sex hormone secretion is temporarily increased at the beginning of administration and then down-regulated after a certain point in time, excessive initial drug release is a factor that must be avoided.
- International Patent Publication No. WO 2005/117830 discloses at least one neutral diacilipid and/or tocopherol, at least one phospholipid, and at least one biocompatible and oxygen-containing discloses an initial formulation containing a low-viscosity organic solvent that It discloses an initial formulation containing. These formulations do not produce lactic acid or glycolic acid degradation products of the polymer system, so pain or inflammation at the injection site is not accompanied, and pharmacologically active substances are continuously released in vivo for about 4 weeks.
- the diacyl lipid which is a key component of the formulation, is a material that is not generally used as an excipient for pharmaceuticals and is not sufficiently secured, and there is a problem that an organic solvent that causes deterioration of the activity of some pharmacologically active substances must be used.
- the present inventors a) sorbitan unsaturated fatty acid ester (sorbitan unsaturated fatty acid ester); b) phospholipids; c) a liquid crystal strengthening agent; and d) a pharmaceutical composition comprising a GnRH derivative as a pharmacologically active substance, in a lipid liquid state in the absence of an aqueous fluid, and forming liquid crystals in an aqueous fluid (Korean Application No. 10-2012-0157583) ).
- the sustained-release lipid initial formulation according to the present invention has equal or superior safety and biodegradability in animal testing (in vivo) compared to the existing initial formulation, and the pharmaceutical composition comprising a pharmacologically active substance releases the drug was confirmed.
- the present inventors repeated research and added water to the initial sustained-release lipid initial preparation containing the GnRH derivative in advance to form a liquid crystal gel immediately after administration of the liquid injection, thereby significantly improving the initial release rate and sustained-release properties of the drug.
- Depot formulation invention was completed.
- polyoxyethylene sorbitan fatty acid ester and polyoxyethylene vitamin E derivative are substances in which polyoxyethylene, a hydrophilic polymer, is combined with sorbitan fatty acid ester and vitamin E, respectively, and the structure of the original sorbitan fatty acid ester and vitamin E is different. It is completely different and different from the constituents of the present invention in that it is a material used as a hydrophilic surfactant using the properties of polyoxyethylene.
- WO 2012/160212 discloses 20-80% of at least one diacilipid and/or tocopherol, 20-80% of at least one phospholipid, and 5-35% of at least one biocompatible organic An alcohol solvent, an aqueous solution of 20% or less, and at least one dual amylin receptor/GLP-1 receptor agonist drug are disclosed in the initial formulation. Disclosed is an initial formulation comprising one phospholipid, a low-viscosity organic solvent containing at least one oxygen, and at least one opioid drug. These formulations do not produce lactic acid or glycolic acid degradation products of the polymer system, so pain or inflammation at the injection site is not accompanied, and pharmacologically active substances are continuously released in vivo.
- WO 2005/074896 discloses a composition that releases a GnRH agonist or a salt thereof for a long period of time as PLGA microcapsules containing an aqueous solution.
- the composition of this patent is different from the present invention in that the composition of the patent is a PLGA microparticle formulation, which is a sustained release formulation completely different from the present invention, and the aqueous channel inside the PLGA microparticles is used for containing a water-soluble drug.
- Patent Document 1 International Patent Publication No. WO 2005/074896
- Patent Document 2 International Patent Publication No. WO 2005/117830
- Patent Document 3 International Patent Publication No. WO 2006/075125
- Patent Document 4 International Patent Publication No. WO 2012/160212
- Patent Document 5 US Registered Patent Publication No. 5,480,656
- Patent Document 6 US Registered Patent Publication No. 6,773,714
- Patent Document 7 US Registered Patent Publication No. 7,731,947
- Patent Document 8 US Registered Patent Publication No. 7,871,642
- Patent Document 9 US Registered Patent Publication No. 5,888,533
- An object of the present invention is to remarkably improve safety by using a sorbitan unsaturated fatty acid ester having two or more -OH (hydroxy groups) in a polar head group as a composition, and it is liquid in the absence of aqueous fluid, so it is easy to apply a pharmaceutical formulation in a dosage form.
- An object of the present invention is to provide an injectable composition that increases the sustained-release properties of a GnRH derivative used as a pharmacologically active material in vivo by forming a liquid crystal in an aqueous fluid phase.
- An object of the present invention is to remarkably improve safety by using a sorbitan unsaturated fatty acid ester having two or more -OH (hydroxy groups) in a polar head group as a composition, and it is liquid in the absence of aqueous fluid, so it is easy to apply a pharmaceutical formulation in a dosage form.
- An object of the present invention is to provide an injectable composition that increases the sustained-release properties of a GnRH derivative used as a pharmacologically active material in vivo by forming a liquid crystal in an aqueous fluid phase.
- Another object of the present invention is to provide an injectable composition capable of improving injection pain, inflammation, and high initial release concentration, which the conventional sustained-release formulations cannot overcome because it is injectable in a liquid form.
- the present invention provides a) a sorbitan unsaturated fatty acid ester having two or more -OH (hydroxyl) groups in the polar head group; b) phospholipids; c) a liquid crystal hardener that does not have an ionizer, and the hydrophobic portion has a triacyl group having 15 to 40 carbon atoms or a carbon ring structure; d) water; and e) a gonadotropin-releasing hormone (GnRH) derivative as a pharmacologically active substance, which is liquid before injection and forms liquid crystals after injection.
- GnRH gonadotropin-releasing hormone
- R has 4 to 30 carbon atoms and means an alkyl ester group including at least one double bond.
- the conventional liquid crystalline material is difficult to apply to drug development due to the following disadvantages of each.
- oleyl glycerate (OG) and phytanyl glycerate (PG) can form liquid crystals well, they are not used as excipients for pharmaceuticals due to their relatively high toxicity. Although this is possible, it has a disadvantage in that it cannot form sustained-release liquid crystals required for pharmaceuticals due to its low ability to form liquid crystals.
- GDO glycerin diolate
- WO 2005/117830 International Patent Publication No. WO 2005/117830 described above is in the form of a glyceride having a diacyl group, and although glycerin is used as a polar head part, it is generally not used as an excipient for pharmaceuticals because of its safety. There is a problem in that the material is not sufficiently secured.
- liquid crystals formed by sorbitan unsaturated fatty acid esters are not only very advantageous for sustained release of the active material, but also have superior safety compared to existing liquid crystal forming materials.
- liquid crystals formed by sorbitan unsaturated fatty acid esters are not only very advantageous for sustained release of the active material, but also have superior safety compared to existing liquid crystal forming materials.
- biodegradability is an essential element.
- biodegradability is a very important factor.
- the sustained-release effect is shown for 1 week, ideally after 1 week, it is desirable that the injected PLGA is decomposed and disappears in the living body. There is a problem that persists without decomposition from up to several months. Therefore, it is clear that the sorbitan unsaturated fatty acid ester of the present invention, which has excellent sustained-release properties, secures safety, and is also excellent in biodegradability, is a new liquid crystal forming material having a very high industrial value.
- the sorbitan unsaturated fatty acid ester of the present invention is a vegetable oil (eg, palm oil, castor oil, olive oil, peanut oil, rapeseed oil, corn oil, sesame oil, cottonseed oil, soybean oil, sunflower oil, safflower oil, linseed oil, etc.), Sorbitan monoester, sorbitan sesquiester, sorbitan derived from fatty acids obtainable from animal fats and oils (eg milk fat, pork fat and tallow) as well as whale oil and fish oil.
- One or more sorbitan diesters and mixtures thereof may be selected.
- the sorbitan monoester is one fatty acid group ester-bonded with sorbitan, sorbitan monooleate (sorbitan monooleate), sorbitan monolinoleate (sorbitan monolinoleate), sorbitan monopalmitolate (sorbitan) monopalmitoleate), sorbitan monomyristoleate, and at least one mixture thereof may be selected.
- the sorbitan sesquiester is an ester bond of 1.5 fatty acid groups on average to sorbitan, and includes sorbitan sesquioleate, sorbitan sesquilinoleate, sorbitan sesquipalmi. Tolate (sorbitan sesquipalmitoleate), sorbitan sesquimyristoleate (sorbitan sesquimyristoleate), and at least one mixture thereof may be selected.
- the sorbitan diester is an ester bond of two fatty acid groups to sorbitan, sorbitan dioleate, sorbitan dilinoleate, sorbitan dipalmitoleate ), sorbitan dimyristoleate, and mixtures thereof.
- Sorbitan unsaturated fatty acid ester is sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate ), sorbitan sesquioleate, and mixtures thereof are preferably used.
- the phospholipid of the present invention is a material that has been essentially used for the production of a lamellar structure such as a liposome in the prior art, but independently has a non-lamellar phase structure in a liquid phase Crystals cannot be formed.
- the phospholipid plays a role in stabilizing the liquid crystal by participating in the non-lamellar structure triggered by the sorbitan unsaturated fatty acid ester, which is the liquid crystal forming agent of the present invention.
- the phospholipid of the present invention is a plant or animal-derived form, and specifically has an alkyl ester group having 4 to 30 saturated or unsaturated carbon atoms, and phosphatidylcholine, phosphatidylethanolamine depending on the structure of the polar head part. (phosphatidylethanolamine), phosphatidylserine, phosphatidylglycerine, phosphatidylinositol and phosphatidic acid, one or more sphingomyelin and mixtures thereof may be selected.
- phospholipid is a form derived from plants or animals such as soybean or egg, and the alkyl ester group bonded to phospholipid is mono- and dipalmitoyl, mono- and dimyristoyl (mono- and dimyristoyl). and dimyristoyl), mono- and dilauryl, mono- and distearyl, saturated fatty acid esters or mono- or dilinoleyl, mono- and dioleyl ( There are unsaturated fatty acid esters such as mono- and dioleyl, mono- and dipalmitoleyl, mono- and dimyristoleyl, or saturated fatty acid esters and unsaturated fatty acid esters. may be in the form
- the liquid crystal strengthening agent of the present invention is actually very specific, and can be administered to the human body only through direct and repeated experiments and a material suitable for the living body can be selected.
- the liquid crystal strengthening agent suitable for the composition of the present invention is Each of them had a different molecular structure, so it could not be explained by a single structure.
- the hydrophobic portion does not have an ionizing group such as a carboxyl group or an amine group and has a total carbon number of 15 to 40 bulky tria It was confirmed that the material had a real group or a carbon ring structure.
- the liquid crystal strengthening agent of the present invention is triglyceride, retinyl palmitate, tocopherol acetate, cholesterol, benzyl benzoate, ubiquinone, and One or more of these mixtures may be selected, but the present invention is not limited thereto.
- tocopherol acetate, cholesterol, or a mixture thereof may be the liquid crystal strengthening agent of the present invention.
- the water of the present invention serves to rapidly form a liquid crystal gel immediately after the liquid injection is administered.
- the lipid initial formulation without water draws moisture in the living body and forms a liquid crystal gel very slowly. Because it forms a liquid crystal gel at a slow rate, it spreads widely in the injection site, and in that state, a liquid crystal gel is formed to form a gel with a large surface area or to form a fragmented gel.
- a liquid crystal gel having a large surface area or fragmented liquid crystal gel causes dumping of the drug at the initial stage of administration, which results in insufficient drug release in the late stage of the sustained-release period, making it difficult to maintain stable sustained-release properties for a long period of time.
- the initial formulation of the lipid contains water, it rapidly forms a gel upon administration to the tissue to lower the initial release rate of the drug, thereby providing stable sustained release of the drug.
- water may be added as water for injection, distilled water, buffer, or a mixture of two or more selected among them.
- GnRH analogues are structurally similar to GnRH, but act differently in the body. In general, GnRH performs a biological function of inducing the production of sex steroids in the body through pulsatile secretion, but GnRH derivatives are used to strongly inhibit the production of sex steroids in the body for a certain period of time.
- GnRH derivatives can be classified into agonists or antagonists according to their mechanism of action.
- a therapeutic dose of a GnRH agonist When a therapeutic dose of a GnRH agonist is administered into the body, the GnRH agonist initially binds to the GnRH receptor of the pituitary gonadotropin and promotes the biosynthesis and secretion of follicle-stimulating hormone (FSH) and progesterone (LH).
- FSH follicle-stimulating hormone
- LH progesterone
- continuous administration of a GnRH agonist depletes gonadotropin, while down-regulating the GnRH receptor has the function of inhibiting the biosynthesis and secretion of follicle stimulating hormone (FSH) and progesterone (LH).
- GnRH derivatives can be used for prostate cancer, breast cancer, ovarian cancer, endometriosis, fibroids of the uterus, polycystic ovaryosis, hirsutism, precocious puberty, gonadotropic pituitary adenoma, sleep apnea, irritable bowel syndrome, and premenstrual syndrome.
- GnRH agonist that can be used as a pharmacologically active material of the present invention is leuprolide, goserelin, triptorelin, nafarelin, buserelin ), histrelin, deslorelin, meterelin, gonadrelin, or a pharmacologically acceptable salt thereof may be selected.
- one or more pharmacologically active substances may be selected from leuprolide, goserelin, and pharmacologically acceptable salts thereof.
- GnRH antagonists competitively respond to the GnRH receptor of the pituitary gonadotropin and block the binding of GnRH in the body, thereby inhibiting the biosynthesis and secretion of follicle-stimulating hormone (FSH) and progesterone (LH).
- FSH follicle-stimulating hormone
- LH progesterone
- GnRH antagonists that can be used as pharmacologically active substances of the present invention are degarelix, abarelix, ganirelix, cetrorelix and their pharmacologically acceptable salts.
- one or more pharmacologically active substances may be selected from degarelix and pharmacologically acceptable salts thereof.
- composition for injection of the present invention may further include a solvent in addition to a) to e).
- a solvent may be ethanol, dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate, methylpyrrolidone or propylene glycol, and these may be used alone or in combination of two or more.
- the weight ratio of component a) and component b) suitable for the desired liquid crystal of the composition for injection of the present invention is 10:1 to 1:10, specifically, 5:1 to 1:5.
- the weight ratio of component a)+b) and component c) is from 100:1 to 1:1, and may be, for example, from 50:1 to 2:1.
- the sustained-release effect by the liquid crystal desired in the present invention may be good, and it is possible to control the sustained-release pattern by controlling their ratio.
- the weight ratio of components a) + b) + c) and d) suitable for the desired liquid crystal of the injectable composition of the present invention is 99:1 to 1:1, for example, 99:1 to 90:10 or 75:25 to 62.5:37.5.
- the weight ratio of components a) + b) + c) + d) and component e) suitable for the desired liquid crystal of the injectable composition of the present invention is 10000:1 to 1:1, for example, 1000:1 to It is 1:1.
- the content of one component expressed as “wt%” means that the weight of the component accounts for 100% of the total weight of the injectable composition.
- the injectable composition of the present invention may include an extra solvent along with components a) to e).
- the injectable composition of the present invention is a) 9 to 90% by weight; b) 9 to 90% by weight; c) 0.1 to 50% by weight; d) 0.5 to 50% by weight and e) 0.01 to 50% by weight.
- the injectable composition of the present invention comprises a) 9 to 50% by weight; b) 18 to 60% by weight; c) 1 to 36% by weight; d) 0.5 to 50% by weight; and e) 0.1 to 45% by weight.
- the injectable composition of the present invention comprises a) 9 to 50% by weight; b) 18 to 60% by weight; c) 1 to 36% by weight; d) 0.5 to 10.5% by weight; and e) 0.1 to 45% by weight.
- the injectable composition of the present invention comprises a) 9 to 50% by weight; b) 18 to 60% by weight; c) 1 to 36% by weight; d) 2.5 to 10.5% by weight; and e) 0.1 to 45% by weight.
- the composition for injection of the present invention comprises a) 9 to 50% by weight; b) 18 to 60% by weight; c) 1 to 36% by weight; d) 0.5 to 10.5% by weight or 25 to 37.5% by weight; and e) 0.1 to 45 wt% of leuprolide or a pharmaceutically acceptable salt thereof.
- Sorbitan unsaturated fatty acid ester (sorbitan unsaturated fatty acid ester), phospholipid, liquid crystal strengthening agent, water, and pharmacologically active substances were added at the same weight as in Table 1 below.
- Comparative Examples 2 and 10 of the present invention the gel properties in the subcutaneous tissue of the mini pig were confirmed.
- the experiment was performed by administering 0.3 mL each of the compositions of Comparative Examples 2 and 10 using a disposable syringe under the back skin of a mini pig (male) weighing about 15 kg. After 7 days had elapsed after administration, the administration site was excised, and the results of comparative observation of the gel properties are shown in FIG. 3 .
- Example 13 lowered the initial drug dumping phenomenon and maintained a higher drug blood concentration than the composition of Comparative Example 3 for 1 month while the drug remained in the gel formulation.
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Abstract
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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CN202180046461.0A CN115867258A (zh) | 2020-06-30 | 2021-06-29 | 包含GnRH衍生物的可注射组合物 |
AU2021299156A AU2021299156A1 (en) | 2020-06-30 | 2021-06-29 | Injectable composition comprising GnRH analogue |
US18/010,399 US20230248801A1 (en) | 2020-06-30 | 2021-06-29 | INJECTABLE COMPOSITION COMPRISING GnRH ANALOGUE |
CA3180468A CA3180468A1 (fr) | 2020-06-30 | 2021-06-29 | Composition injectable comprenant des derives de gnrh |
EP21833046.2A EP4173614A1 (fr) | 2020-06-30 | 2021-06-29 | Composition injectable comprenant des dérivés de gnrh |
MX2022016437A MX2022016437A (es) | 2020-06-30 | 2021-06-29 | Composicion inyectable que comprende un analogo de gnrh. |
JP2022581316A JP2023532107A (ja) | 2020-06-30 | 2021-06-29 | Gnrh誘導体を含む注射用組成物 |
BR112022025817A BR112022025817A2 (pt) | 2020-06-30 | 2021-06-29 | Composição injetável que compreende análogo de gnrh |
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WO2024003291A1 (fr) * | 2022-06-30 | 2024-01-04 | Virbac | Utilisation de desloréline dans la castration chimique d'un mammifère non humain lié à une interaction pharmacocinétique/pharmacodynamique |
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2021
- 2021-06-29 US US18/010,399 patent/US20230248801A1/en active Pending
- 2021-06-29 CA CA3180468A patent/CA3180468A1/fr active Pending
- 2021-06-29 KR KR1020210084599A patent/KR102628523B1/ko active IP Right Grant
- 2021-06-29 AU AU2021299156A patent/AU2021299156A1/en active Pending
- 2021-06-29 CN CN202180046461.0A patent/CN115867258A/zh active Pending
- 2021-06-29 JP JP2022581316A patent/JP2023532107A/ja active Pending
- 2021-06-29 MX MX2022016437A patent/MX2022016437A/es unknown
- 2021-06-29 EP EP21833046.2A patent/EP4173614A1/fr active Pending
- 2021-06-29 WO PCT/KR2021/008187 patent/WO2022005169A1/fr active Application Filing
- 2021-06-29 BR BR112022025817A patent/BR112022025817A2/pt unknown
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AU2021299156A1 (en) | 2023-01-19 |
KR102628523B1 (ko) | 2024-01-24 |
CA3180468A1 (fr) | 2022-01-06 |
US20230248801A1 (en) | 2023-08-10 |
BR112022025817A2 (pt) | 2023-01-10 |
EP4173614A1 (fr) | 2023-05-03 |
CN115867258A (zh) | 2023-03-28 |
KR20220002140A (ko) | 2022-01-06 |
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